Assessing Memory in an Aldehyde Dehydrogenase 2 Knockout Model of Alzheimer's Disease

Abstract

The study of Alzheimer’s Disease (AD) has been hindered by the absence of animal models of late-onset/age-related AD (also termed sporadic AD) (95% of AD cases) since current transgenic mouse models exhibit pathological changes dependent on overexpression of mutant human genes linked to early-onset, familial AD (5% of cases). Oxidative stress is considered to be a causative factor in age-related AD, and we have found that aldehyde dehydrogenase 2 (Aldh2) null mice exhibit not only oxidative stress, but also display many AD-like pathologies. The current study used behavioral analysis to assess whether Aldh2-/- mice also exhibit memory and cognition deficits. Male and female wild type and Aldh2-/- mice were tested monthly beginning at three months of age, using the open field novel object recognition test (a measure of recognition memory), as well as spontaneous alternations in the Y-maze (a measure of spatial working memory). In both tasks, significant decreases in performance occurred in Aldh2-/- mice by 3.5-4 months of age, and this progressively declined over the next three months compared to wild type mice. Sex-related differences in memory impairment were not observed. These results, together with the findings that AD-like pathologies are also present, suggest that Aldh2-/- mice represent a new, oxidative stress-based model of age-related cognitive impairment and AD. This model may prove useful both for assessing AD therapeutics and for gaining better insight into the pathogenesis of AD.